G protein-coupled receptor kinase 2 promotes cardiac hypertrophy.
G protein-coupled receptor kinase 2 promotes cardiac hypertrophy.
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DOI：
10.1371/journal.pone.0182110
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发表时间：
2017
期刊：
影响因子：
3.7
通讯作者：
Raake PW
中科院分区：
文献类型：
--
作者：
Schlegel P;Reinkober J;Meinhardt E;Tscheschner H;Gao E;Schumacher SM;Yuan A;Backs J;Most P;Wieland T;Koch WJ;Katus HA;Raake PW
蛋白活性增加和G蛋白偶联受体激酶2(GRK2)表达上调是心脏应激和心力衰竭的标志。抑制GRK2可改善各种动物心力衰竭模型的心功能和存活率，并减少心脏重构。本研究旨在探讨GRK2在心肌肥厚中的作用及其可能的分子机制。在小鼠中，我们观察到横断性主动脉缩窄(TAC)后GRK2mRNA和蛋白水平的增加。与野生型相比，条件性GRK2基因敲除小鼠在TAC手术后6周表现出肥大反应减弱，并保留了心室几何结构。在体外培养的乳鼠心肌细胞中，血管紧张素II和苯肾上腺素刺激可增强GRK2的表达，增强蛋白激酶B(PKB或AKT)的信号转导，进而抑制糖原合成酶3β(GSK3β)，从而促进活化T细胞的核内积聚和核因子的激活。GRK2过表达诱导的心肌细胞肥大增加了GRK2与磷脂酰肌醇3-激酶γ(PI3Kγ)的胞内相互作用。此外，抑制PI3KNFAT和GRK2AKT的激活可阻止γ的激活，从而抑制NFAT活性，减少心肌细胞肥大。我们的数据表明，GRK2的表达增强通过GRK2-PI3Kγ介导的Akt磷酸化和随后的Gsk3β失活而触发心肌肥大，从而导致NFAT活性增强。
The increase in protein activity and upregulation of G-protein coupled receptor kinase 2 (GRK2) is a hallmark of cardiac stress and heart failure. Inhibition of GRK2 improved cardiac function and survival and diminished cardiac remodeling in various animal heart failure models. The aim of the present study was to investigate the effects of GRK2 on cardiac hypertrophy and dissect potential molecular mechanisms. In mice we observed increased GRK2 mRNA and protein levels following transverse aortic constriction (TAC). Conditional GRK2 knockout mice showed attenuated hypertrophic response with preserved ventricular geometry 6 weeks after TAC operation compared to wild-type animals. In isolated neonatal rat ventricular cardiac myocytes stimulation with angiotensin II and phenylephrine enhanced GRK2 expression leading to enhanced signaling via protein kinase B (PKB or Akt), consecutively inhibiting glycogen synthase kinase 3 beta (GSK3β), such promoting nuclear accumulation and activation of nuclear factor of activated T-cells (NFAT). Cardiac myocyte hypertrophy induced by in vitro GRK2 overexpression increased the cytosolic interaction of GRK2 and phosphoinositide 3-kinase γ (PI3Kγ). Moreover, inhibition of PI3Kγ as well as GRK2 knock down prevented Akt activation resulting in halted NFAT activity and reduced cardiac myocyte hypertrophy. Our data show that enhanced GRK2 expression triggers cardiac hypertrophy by GRK2-PI3Kγ mediated Akt phosphorylation and subsequent inactivation of GSK3β, resulting in enhanced NFAT activity.
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